Oral testosterone ester formulations and methods of treating testosterone deficiency comprising same

ABSTRACT

A pharmaceutical formulation of testosterone undecanoate is provided. Methods of treating a testosterone deficiency or its symptoms with the inventive formulations are also provided.

FIELD OF THE INVENTION

The present invention relates generally to oral formulations oftestosterone esters for the treatment of testosterone deficiency. Moreparticularly, the present invention relates to pharmaceuticalcomposition comprising testosterone undecanoate (TU) with enhanced andextended absorption and pharmacokinetics.

BACKGROUND OF THE INVENTION

Testosterone (T) is a primary androgenic hormone produced in theinterstitial cells of the testes and is responsible for normal growth,development and maintenance of male sex organs and secondary sexcharacteristics (e.g., deepening voice, muscular development, facialhair, etc.). Throughout adult life, testosterone is necessary for properfunctioning of the testes and its accessory structures, prostate andseminal vesicle; for sense of well-being; and for maintenance of libido,erectile potency.

Testosterone deficiency—insufficient secretion of T characterized by lowserum T concentrations—can give rise to medical conditions (e.g.,hypogonadism) in males. Symptoms associated with male hypogonadisminclude impotence and decreased sexual desire, fatigue and loss ofenergy, mood depression, regression of secondary sexual characteristics,decreased muscle mass, and increased fat mass. Furthermore, hypogonadismin men is a risk factor for osteoporosis, metabolic syndrome, type IIdiabetes and cardiovascular disease.

Various testosterone replacement therapies are commercially availablefor the treatment of male hypogonadism. Pharmaceutical preparationsinclude both testosterone and testosterone derivatives in the form ofintramuscular injections, implants, oral tablets of alkylated T (e.g.,methyltestosterone), topical gels, or topical patches. All of thecurrent T therapies, however, fail to adequately provide an easy andclinically effective method of delivering T. For example, intramuscularinjections are painful and are associated with significant fluctuationsin serum T levels between doses; T patches are generally associated withlevels of T in the lower range of normal (i.e., clinically ineffective)and often cause substantial skin irritation; and T gels have beenassociated with unsafe transfer of T from the user to women andchildren. As well, the sole “approved” oral T therapy,methyltestosterone, is associated with a significant occurrence of livertoxicity. Over time, therefore, the current methods of treatingtestosterone deficiency suffer from poor compliance and thusunsatisfactory treatment of men with low T.

Testosterone and its esters are poorly bioavailable—owing to extensivefirst pass intestinal and hepatic metabolism—or ineffective—due to aninability of the body to liberate testosterone from its testosteroneprodrug. For example, testosterone and testosterone esters with sidechains of less than 10 carbons in length are primarily absorbed via theportal circulation resulting in substantial, if not total, first passmetabolism. Fatty acid esters of long carbon chains (i.e., 14 or morecarbons) may be absorbed by intestinal lymphatics, but the longer thefatty acid chain length, the slower the rate and extent of hydrolysis ofthe ester by esterases to liberate testosterone thus resulting in poor(i.e., clinically ineffective) pharmacological activity.

Other than selection of a testosterone ester, the formulation of thetestosterone ester presents unique challenges. The gastrointestinalenvironment is decidedly aqueous in nature, which requires that drugsmust be solubilzed for absorption. However, testosterone andparticularly its esters are extremely insoluble in water and aqueousmedia, and even if the T or T ester is solubilized initially in theformulation, the formulation must be able to maintain the drug in asoluble or dispersed form without precipitation or, otherwise, comingout of solution in vivo (although such a property can be tested invitro, for example, by mixing the contents of a formulation in simulatedintestinal fluid). Furthermore, an oral T formulation must, effectivelyrelease T or T ester according to a desired release profile. Hence, aneffective formulation of T or T ester must balance good solubility withoptimum release and satisfaction of a targeted plasma or serumconcentration profile.

For these reasons, among others, no oral formulation of testosterone ortestosterone esters has been approved by the United States Food and DrugAdministration (FDA) to date. In fact, the only oral testosteroneproduct ever approved to date by the FDA is methyltestosterone (in whicha methyl group covalently bound to a testosterone “nucleus” at the C-17position to inhibit hepatic metabolism; note, also, thatmethyltestosterone is not a prodrug of testosterone) and this approvaloccurred several decades ago. Unfortunately, use of methyltestosteronehas been associated with a significant incidence of liver toxicity, andit is rarely prescribed to treat men with low testosterone.

As noted above, fatty acid esters of testosterone provide yet anothermode of potential delivery of testosterone to the body (i.e., as a“prodrug”). Once absorbed, testosterone can be liberated from its estervia the action of non-specific tissue and plasma esterases. Furthermore,by increasing the relative hydrophobicity of the testosterone moiety andthe lipophilicity of the resulting molecule as determined by itsn-octanol-water partition coefficient (log P) value, such prodrugs canbe absorbed, at least partially, via the intestinal lymphatics, thusreducing first-pass metabolism by the liver. In general, lipophiliccompounds having a log P value of at least 5 and oil solubility of atleast 50 mg/mL are transported primarily via the lymphatic system.

Despite their promise, prodrugs of testosterone, including testosteroneesters, have not been formulated in a manner to achieve effective andsustained serum testosterone levels at eugonadal levels (i.e., averageserum T concentration falling in the range of about 300-1100 ng/dL). Infact, an orally administered pharmaceutical preparation of atestosterone prodrug, including testosterone esters, has yet to beapproved by the FDA.

Hence, there remains a need for an oral formulation of a testosteroneester, which provides optimum serum testosterone levels that areclinically effective to treat hypogonadal men (i.e., those with a serumT concentration of ≤300 ng/dL) over an extended period of time.

SUMMARY OF THE INVENTION

In one embodiment of the present invention, an oral pharmaceuticalcomposition is provided comprising testosterone undecanote solubilizedin a carrier comprising at least one lipophilic surfactant and at leastone hydrophilic surfactant in a total lipohilic surfactant to totalhydrophilic surfactant ratio (w/w) falling in the range of about 6:1 to3.5:1, which composition, upon once- or twice-daily oral administration,provides an average serum testosterone concentration at steady statefalling in the range of about 300 to about 1100 ng/dL. Thepharmaceutical composition provides a C_(max) that, when administeredwith a meal, does not exceed 2500 ng/dL, preferably does not exceed 1800ng/dL, and most preferably does not exceed 1500 ng/dL.

According to a preferred embodiment, the at least one hydrophilicsurfactant comprises Cremophor RH 40 (polyoxyethyleneglyceroltrihydroxystearate); the at least one lipophilic surfactant comprisesoleic acid. The pharmaceutical compositions of the invention maycomprise 18 to 22 percent by weight of the solubilized testosteroneundecanoate, and may further be substantially free of a monohydricalcohols such as ethanol.

In another embodiment of the invention, a dosage form of testosteroneundecanoate is provided comprising testosterone undecanote solubilizedin a carrier comprising at least one lipophilic surfactant and at leastone hydrophilic surfactant, which dosage form, upon once- or twice-dailyoral administration to a subject suffering from hypogonadism or itssymptoms, provides an average serum testosterone concentration at steadystate falling in the range of about 300 to about 1100 ng/dL, whileavoiding an occurrence of a C_(max) value that exceeds 2500 ng/dL, morepreferably avoiding an occurrence of a C_(max) value that exceeds 1800ng/dL, and most preferably avoiding an occurrence of a C_(max) valuethat exceeds 1500 ng/dL.

In yet another embodiment of the present invention, a pharmaceuticalcomposition is provided comprising testosterone undecanoate solubilizedin a carrier comprising at least one lipophilic surfactant and at leastone hydrophilic surfactant, which composition, upon oral administrationwith a meal having a fat content ranging from as low as 20 wt % to ashigh as 50 wt %, provides an average serum testosterone concentrationthat is statistically insignificant to that observed upon oraladministration with a meal having a fat content of about 30 wt %.

In still yet another embodiment of the invention, a pharmaceuticalcomposition is provided comprising testosterone undecanote solubilizedin a carrier comprising at least one lipophilic surfactant and at leastone hydrophilic surfactant in a total lipohilic surfactant to totalhydrophilic surfactant ratio (w/w) falling in the range of about 6:1 to3.5:1, which composition, upon once- or twice-daily oral administration,provides a serum testosterone rapid phase half-life of about 5 hours anda serum testosterone terminal high-life of about 29 hours.

In still yet another embodiment of the invention, a pharmaceuticalcomposition is provided comprising testosterone undecanote solubilizedin a carrier comprising at least one lipophilic surfactant and at leastone hydrophilic surfactant in a total lipophilic surfactant to totalhydrophilic surfactant ratio (w/w) falling in the range of about 6:1 to3.5:1, which composition, upon once- or twice-daily oral administrationto a subject suffering from testosterone deficiency or its symptoms,provides a mean serum testosterone concentration at day 30 of a dailytreatment regimen, which is substantially the same as that observed onday 7. According to the invention, the mean serum testosteroneconcentration obtained at day 30 of a daily treatment regimen may alsobe substantially the same as that observed on day 60.

In another embodiment of the invention, a method of treatingtestosterone deficiency or its symptoms is provided comprising orallyadministering to a subject suffering from testosterone deficiency or itssymptoms an effective amount of a pharmaceutical composition comprisingtestosterone undecanote solubilized in a carrier comprising at least onelipophilic surfactant and at least one hydrophilic surfactant in a totallipophilic surfactant to total hydrophilic surfactant ratio (w/w)falling in the range of about 6:1 to 3.5:1 to provide an average serumtestosterone concentration at steady state falling in the range of about300 to about 1100 ng/dL. The composition may be administered once dailyor twice daily, and can give rise to a C_(max) value falling in therange of about 900 to 1100 ng/dL.

According to the method, the composition may be administered with a mealcomprising at least 20 wt % fat. The method can give rise tosubstantially no diurnal testosterone pharmacokinetic variation, anaverage serum T_(max) value falling in the range of about 3 to 7 hoursafter oral administration, and substantially no significant decline insteady state serum testosterone response is observed upon repeat dosing.

In a preferred embodiment of the present invention, a pharmaceuticalcomposition is provided comprising:

(a) 15-25 percent by weight of a solubilized testosterone undecanoate;

(b) 12-18 percent by weight of at least one hydrophilic surfactant;

(c) 50-65 percent by weight of at least one lipophilic surfactant;

(d) 10-15 percent by weight of a mixture of borage oil and peppermintoil,

which composition may be free of monohydric alcohols generally,specifically, ethanol and, upon oral administration to a subject in needthereof, gives rise to a serum testosterone half-life (T_(1/2)) fallingin the range of about 10 hours to about 18 hours. Cremophor RH40 is apreferred hydrophilic surfactant and a preferred lipophilic surfactantis oleic acid. Borage oil and peppermint oil are both consideredlipophilic surfactants.

In a particularly preferred embodiment, the composition comprises:

(a) 18-22 percent by weight of a solubilized testosterone undecanoate;

(b) 15-17 percent by weight of at least one hydrophilic surfactant;

(c) 50-55 percent by weight of at least one lipophilic surfactant; and;

(d) 10-15 percent by weight of a mixture of borage oil and peppermintoil.

The ratio of borage oil to peppermint oil may range from 8:1 to 3:1;preferably from 6:1 to 5:1; most preferably from 5:1 to 4:1. Inaddition, to Cremophor RH40, Solutol HS-15, Tween 80 and TPGS arepreferred hydrophilic surfactants; and, in addition to oleic acid,Glycerol monoleate, propylene glycol laurate and Capmul MCM arepreferred lipophilic surfactants. Combinations of two or more lipophilicsurfactants and two or more hydrophilic surfactants are alsocontemplated.

In another embodiment of the present invention, a method of treatingtestosterone deficiency is provided, the method comprising orallyadministering to a hypogonadal subject an effective amount of apharmaceutical composition comprising:

(a) 15-25 percent by weight of a solubilized testosterone undecanoate;

(b) 12-18 percent by weight of one or more hydrophilic surfactants;

(c) 50-65 percent by weight of one or more lipophilic surfactants;

(d) 10-15 percent by weight of a mixture of borage oil and peppermintoil,

and free of ethanol, whose once- or twice-daily oral administrationgives rise to an average (or a mean) steady state serum testosteroneconcentration, Cave, falling in the range of about 300 and about 1100ng/dL in the subject. The composition may optionally be administeredwith a meal whose fat content ranges from about 15 wt % to about 25 wt %or more. According to the method, any one or all of the followingpharmacokinetic parameters may be achieved in the subject:

(a) serum testosterone C_(max) within 900 and 1100 ng/dL in the subject;

(b) substantially no diurnal testosterone pharmacokinetic variation;

(c) serum T_(max) 3 to 7 hours after administering the composition; and

(d) substantially no decline in steady state serum testosterone responseis observed upon repeat dosing.

In this respect, before explaining at least one embodiment of theinvention in detail, it is to be understood that the invention is notlimited in its application to the details of construction and to thearrangements of the components set forth in the following description orillustrated in the drawings. The invention is capable of embodiments inaddition to those described and of being practiced and carried out invarious ways. Also, it is to be understood that the phraseology andterminology employed herein, as well as the abstract, are for thepurpose of description and should not be regarded as limiting.

As such, those skilled in the art will appreciate that the conceptionupon which this disclosure is based may readily be utilized as a basisfor the designing of other moieties, methods and systems for carryingout the several purposes of the present invention. For example, someembodiments of the invention may combine TU with other active drugs,including other hormones, in an oral delivery system that, in part,prevents or alleviates symptoms associated with testosterone deficiency.It is important, therefore, that the claims be regarded as includingsuch equivalent constructions, which do not depart from the scope andspirit of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides serum T levels over a 24 hour period of once or twicedaily oral dosing of a TU formulation of the invention.

FIG. 2 shows a serum T response over time in hypogonadal men uponadministration of a formulation of the invention vs. a conventional oralTU formulation comprising TU in oleic acid (Restandol).

FIG. 3 provides T_(max) values of serum T levels in subjects havingconsumed meals of varying fat content (as a percentage by weight) priorto oral administration of a TU formulation of the invention.

FIG. 4 provides C_(max) values of serum T levels in subjects havingconsumed meals of varying fat content (as a percentage by weight) priorto oral administration of a TU formulation of the invention.

FIG. 5 provides area under the curve (AUC) values of serum T levels insubjects having consumed meals of varying fat content (as a percentageby weight) prior to oral administration of a TU formulation of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an oral pharmaceutical compositioncomprising TU, which when administered no more than twice a day tohypogonadal males, provides average steady state serum levels(concentrations) of testosterone in such males, which fall within adesired “normal” or eugonadal range (i.e., about 300-1100 ng/dL) whileavoiding the high C_(max) values that are considered by the UnitedStates Food and Drug Administration to be undesirable, if notunacceptable. For instance FDA approval guidelines state that less than85% of treated subjects may have a C_(max) value of 1500 ng/dL orgreater, and that none may have a C_(max) value exceeding 2500 ng/dL.Less than 5% of treated subjects may have a C_(max) value falling in therange of 1800-2500 ng/dL. Moreover, the formulations of the inventionare designed to be self-emulsifying drug delivery systems (SEDDS) sothat a TU-containing emulsion (or dispersion) is formed upon mixing withintestinal fluids in the gastrointestinal tract.

In one embodiment of the present invention, testosterone and/or estersat the C-17 position of the testosterone molecule, alone or incombination with other active ingredients, may be orally delivered usingthe inventive formulation. For example, the combination of testosteroneundecanoate with an orally active inhibitor of Type I or Type II5α-reductase or the combination of testosterone undecanoate with asynthetic progestin may be preferable in some embodiments.

While many of the embodiments of the present invention will be describedand exemplified with the undecanoate acid ester of testosterone (i.e.,TU), other esters of hydrophobic compounds, including T, can be adoptedfor oral delivery based on the teachings of the specification. In fact,it should be readily apparent to one of ordinary skill in the art fromthe teachings herein that the inventive drug delivery systems andcompositions therefrom may be suitable for oral delivery of othertestosterone esters, such as short-chain (C₂-C₆), medium-chain (C₇-C₁₃)and long-chain (C₁₄-C₂₄) fatty acid esters, preferably medium-chainfatty acid esters of testosterone.

The formulations of the present invention comprise a T-ester dissolvedin a mixture comprising one or more lipophilic surfactants and one ormore hydrophilic surfactants. A lipophilic surfactant as defined hereinhas a hydrophilic-lipophilic balance (HLB) value of less than 10, andpreferably less than 5. A hydrophilic surfactant as defined herein hasan HLB value of greater than 10. (HLB is an empirical expression for therelationship of the hydrophilic and hydrophobic groups of a surfaceactive amphiphilic molecule, such as a surfactant. It is used to indexsurfactants and its value varies from about 1 to about 45 and includesboth non-ionic and ionic surfactants. The higher the HLB, the more watersoluble/dispersible the surfactant.)

According to one aspect of the present invention, each of the componentsof the delivery system (i.e., the lipophilic and hydrophilicsurfactants) individually have solubilizing characteristics andcontribute, in part, to solubilizing the active ingredient. Thoselipophilic surfactants that contribute substantially to dissolving thedrug are defined herein as “primary” solvent(s). It should beappreciated, however, that solubility can be affected by the temperatureof the solvent/formulation. Formulations of the present inventioncomprising, for example, about 20% testosterone undecanoate, remainsoluble at or above 30° C., including in the range of 30 to about 40° C.

A hydrophilic surfactant component may be necessary to achieve desirabledispersability of the formulation in the GI tract and release of thedrug. That is, a hydrophilic surfactant, in addition to serving as asecondary solvent, may be required to release the drug from within thelipid carrier matrix, or primary solvent. In this respect, a high HLBsurfactant, such as Cremophor RH40, can generally suffice. The levels(amounts) of the high HLB surfactant can be adjusted to provide optimumdrug release without compromising the solubilization of the activeingredient.

Lipophilic surfactants suitable in drug delivery systems of the presentinvention include:

Fatty acids (C₆-C₂₄, preferably C₁₀-C₂₄, more preferably C₁₄-C₂₄), forexample, octanoic acid, decanoic acid, undecanoic acid, lauric acid,myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid,and linolenic acid. Oleic acid is preferred.

Mono- and/or di-glycerides of fatty acids, such as Imwitor 988 (glycerylmono-/di-caprylate), Imwitor 742 (glyceryl mono-/di-caprylate/caprate),Imwitor 308 (glyceryl mono-caprylate), Imwitor 191 (glycerylmono-stearate), Softigen 701 (glyceryl mono-/di-ricinoleate), Capmul MCM(glyceryl mono-/di-caprylate/caprate), Capmul MCM(L) (liquid form ofCapmul MCM), Capmul GMO (glyceryl mono-oleate), Capmul GDL (glyceryldilaurate), Maisine (glyceryl mono-linoleate), Peceol (glycerylmono-oleate), Myverol 18-92 (distilled monoglycerides from sunfloweroil) and Myverol 18-06 (distilled monoglycerides from hydrogenatedsoybean oil), Precirol ATO 5 (glyceryl palmitostearate) and Gelucire39/01 (semi-synthetic glycerides, i.e., C₁₂₋₁₈ mono-, di- andtri-glycerides). The preferred members of this class of lipophilicsurfactants are the partial glycerides of oleic, palmitic and stearicacids and blends thereof.

Acetic, succinic, lactic, citric and/or tartaric esters of mono- and/ordi-glycerides of fatty acids, for example, Myvacet 9-45 (distilledacetylated monoglycerides), Miglyol 829 (caprylic/capric diglycerylsuccinate), Myverol SMG (mono/di-succinylated monoglycerides), Imwitor370 (glyceryl stearate citrate), Imwitor 375 (glycerylmonostearate/citrate/lactate) and Crodatem T22 (diacetyl tartaric estersof monoglycerides).

Propylene glycol mono- and/or di-esters of fatty acids, for example,Lauroglycol (propylene glycol monolaurate), Mirpyl (propylene glycolmonomyristate), Captex 200 (propylene glycol dicaprylate/dicaprate),Miglyol 840 (propylene glycol dicaprylate/dicaprate) and Neobee M-20(propylene glycol dicaprylate/dicaprate).

Polyglycerol esters of fatty acids such as Plurol oleique (polyglyceryloleate), Caprol ET (polyglyceryl mixed fatty acids) and Drewpol 10.10.10(polyglyceryl oleate).

Castor oil ethoxylates of low ethoxylate content (HLB<10) such as Etocas5 (5 moles of ethylene oxide reacted with 1 mole of castor oil) andSandoxylate 5 (5 moles of ethylene oxide reacted with 1 mole of castoroil).

Acid and ester ethoxylates formed by reacting ethylene oxide with fattyacids or glycerol esters of fatty acids (HLB<10) such as Crodet 04(polyoxyethylene (4) lauric acid), Cithrol 2MS (polyoxyethylene (2)stearic acid), Marlosol 183 (polyoxyethylene (3) stearic acid) andMarlowet G12DO (glyceryl 12 EO dioleate).

Sorbitan esters of fatty acids, for example, Span 20 (sorbitanmonolaurate), Crill 1 (sorbitan monolaurate) and Crill 4 (sorbitanmono-oleate).

Transesterification products of natural or hydrogenated vegetable oiltriglyceride and a polyalkylene polyol (HLB<10), e.g. Labrafil M1944CS(polyoxyethylated apricot kernel oil), Labrafil M2125CS(polyoxyethylated corn oil) and Gelucire 37/06 (polyoxyethylatedhydrogenated coconut). Labrafil M1944CS is preferred.

Alcohol ethyoxylates (HLB<10), e.g. Volpo N3 (polyoxyethylated (3) oleylether), Brij 93 (polyoxyethylated (2) oleyl ether), Marlowet LA4(polyoxyethylated (4) lauryl ether).

Pluronics, for example, Polyoxyethylene-polyoxypropylene co-polymers andblock co-polymers (HLB<10) e.g. Synperonic PE L42 (HLB=8) and SynperonicPE L61 (HLB=3).

Mixtures of suitable lipophilic surfactants, such as those listed above,may be used if desired, and in some instances are found to beadvantageous.

Any pharmaceutically acceptable hydrophilic surfactant (i.e., having anHLB value greater than 10) may be used in the present invention. Somenon-limiting examples include:

Castor oil or hydrogenated castor oil ethoxylates (HLB>10), e.g.Cremophor EL (polyoxyethylene (35) castor oil), Cremophor RH40(polyoxyethylene (40) hydrogenated castor oil), Etocas 40(polyoxyethylene (40) castor oil), Nikkol HCO-60 (polyoxyethylene (60)hydrogenated castor oil), Solutol HS-15 (polyethylene glycol 660hydroxystearate), Labrasol (caprylocaproyl macrogol-8 glycerides),α-tocopherol-polyethylene glycol-1000-succinate (TPGS) and ascorbyl-6palmitate. Cremophor RH40 is preferred.

Polyoxyethylene sorbitan fatty acid derivates, e.g. Tween 20(polyoxyethylene (20) monolaureate), Tween 80 (polyoxyethylene (20)monooleate), Crillet 4 (polyoxyethylene (20) monooleate) and Montanox 40(polyoxyethylene (20) monopalmitate). Tween 80 (Polysorbate 80) ispreferred.

Gelucires, preferably Gelucire 50/13 (PEG mono- and diesters of palmiticand stearic acids. (In reference to Gelucires, the first number (i.e.,50) corresponds to the melting point of the material and the second(i.e., 13) to the HLB number.)

Fatty acid ethoxylates (HLB>10), e.g. Myrj 45 (polyoxyethylene (8)stearate), Tagat L (polyoxyethylene (30) monolaurate), Marlosol 1820(polyoxyethylene (20) stearate) and Marlosol OL15 (polyoxyethylene (15)oleate). Myrj 45 is preferred.

Alcohol ethoxylates (HLB>10), e.g. Brij 96 (polyoxyethylene (10) oleylether), Volpo 015 (polyoxyethylene (15) oleyl ether), Mario wet OA30(polyoxyethylene (30) oleyl ether) and Marlowet LMA20 (polyoxyethylene(20) C₁₂-C₁₄ fatty ether).

Polyoxyethylene-polyoxypropylene co-polymers and block co-polymers(HLB>10), that are commercially available under the trade name Pluronicsor Poloxamers, such as Poloxamers 188 and 407 also known as Syperonic PEL44 (HLB=16) and Syperonic F127 (HLB=22), respectively.

Anionic surfactants, e.g. sodium lauryl sulphate, sodium oleate andsodium dioctylsulphosuccinate.

Alkylphenol surfactants (HLB>10), e.g. Triton N-101 (polyoxyethylene(9-10) nonylphenol) and Synperonic NP9 (polyoxyethylene (9)nonylphenol).

As mentioned, in one aspect of the present invention, each of thecomponents of the delivery system (i.e., the lipophilic and hydrophilicsurfactants) individually has solvent characteristics and contributes,in part, to solubilizing the active ingredient. In this way, withoutbeing bound by or limited to theory, the present invention does notrequire additional solvents, such as cosolvents, but these may beoptionally included in the inventive systems and formulations.

Optional cosolvents suitable with the instant invention are, forexample, water, short chain mono-, di-, and polyhydric alcohols, such asethanol, benzyl alcohol, glycerol, propylene glycol, propylenecarbonate, polyethylene glycol with an average molecular weight of about200 to about 10,000, diethylene glycol monoethyl ether (e.g., TranscutolHP), and combinations thereof. Preferably, such cosolvents, especiallyethanol or other monoethanols, are excluded altogether.

Additional oils that may be incorporated in embodiments of the presentinvention include complete glycerol triesters of medium chain (C₇-C₁₃)or long chain (C₁₄-C₂₂) fatty acids with low molecular weight (up to C₆)mono-, di- or polyhydric alcohols. Some examples of oils for use in thisinvention thus include: vegetable oils (e.g., soybean oil, safflowerseed oil, corn oil, olive oil, castor oil, cottonseed oil, arachis oil,sunflower seed oil, coconut oil, palm oil, rapeseed oil, eveningprimrose oil, grape seed oil, wheat germ oil, sesame oil, avocado oil,almond, borage, peppermint and apricot kernel oils) and animal oils(e.g., fish liver oil, shark oil and mink oil).

In other embodiments of the present invention, methods and compositionsfor modulating (i.e., sustaining) the rate of available serumtestosterone by incorporating component(s) that may biochemicallymodulate (1) TU absorption, (2) TU metabolism to T, and/or (3)metabolism of T to dihydrotestosterone (DHT). For example, the inclusionof medium to long chain fatty acid esters can enhance TU absorption. Inthis way, more TU may stave off hydrolysis in the gut and enter theblood stream. In other words, the fatty acid ester may competitivelyinhibit esterases that would otherwise metabolize TU. Examples of otheresters or combinations thereof include botanical extracts or benignesters used as food additives (e.g., propylparben, octylacetate andethylacetate).

Other components that can modulate TU absorption include “natural” andsynthetic inhibitors of 5α-reductase, which is an enzyme present inenterocytes and other tissues that catalyzes the conversion of T to DHT.Complete or partial inhibition of this conversion may both increase andsustain increases serum levels of T after oral dosing with TU whileconcomitantly reducing serum DHT levels. Borage oil, which contains asignificant amount of the 5α-reductase inhibitor, gamma-linolenic acid(GLA), is an example of a “natural” modulator of TU metabolism. Otherthan within borage oil, of course, GLA could be added directly as aseparate component of a TU formulation of the invention. Many naturalinhibitors of 5α-reductase are known in the art (e.g., epigallocatechingallate, a catechin derived primarily from green tea and saw palmettoextract from berries of the Serenoa repens species), all of which may besuitable in the present invention. Non-limiting examples of synthetic5α-reductase inhibitors suitable for use in the present inventioninclude compounds such as finasteride, dutasteride and the like.

In addition to 5α-reductase inhibitors, the present inventioncontemplates the use of inhibitors of T metabolism via other mechanisms.One such point of inhibition may be the cytochrome P450 isozyme CYP3A4,which is present in enterocytes and in liver cells and thus capable ofmetabolizing testosterone. Accordingly, selected embodiments of theinvention, include peppermint oil, which is known to contain componentscapable of inhibiting CYP3A4 activity.

Yet other optional ingredients which may be included in the compositionsof the present invention are those which are conventionally used inoil-based drug delivery systems, e.g., antioxidants such as tocopherol,tocopherol acetate, ascorbic acid, butylhydroxytoluene (BHT), ascorbylpalmitate, butylhydroxyanisole and propyl gallate; pH stabilizers suchas citric acid, tartaric acid, fumaric acid, acetic acid, glycine,arginine, lysine and potassium hydrogen phosphate; thickeners/suspendingagents such as hydrogenated vegetable oils, beeswax, colloidal silicondioxide, mannitol, gums, celluloses, silicates, bentonite; flavoringagents such as cherry, lemon and aniseed flavors; sweeteners such asaspartame, acesulfane K, sucralose, saccharin and cyclamates; etc.

The present inventors have learned that relative proportions of the oneor more lipophilic surfactants and one or more hydrophilic surfactantscan be critical to achieving the desired pharmacokinetics of the presentinvention. More specifically, the inventors have discovered a ratio oftotal lipophilic surfactant and total hydrophilic surfactant, which isnot only able to solubilize a relatively large amount of T-ester (e.g.,greater than 15%, 18%, 20%, 22%, or 25%) but one that is also able toprovide optimum release of the T-ester from within the formulation.Preferably, the total oil (e.g., oleic acid+borage oil+peppermint oil,all of which are considered lipophilic surfactants) to hydrophilicsurfactant ratio (w/w) falls in the range of about 6:1 to 1:1, 6:1 to3.1, 6:1 to 3.5:1, or 6:1 to 4:1; and more preferably, from about 5:1 to3:1, and most preferably, from about 4:1 to 3:1.

The following relative concentrations, by weight, are preferred (thepercentages are based on the total weight of the formulation):

Hydrophilic surfactant: 10-20%, more preferably 12-18%, and mostpreferably 15-17%.

Lipophilic surfactant: 50-70%, more preferably 50-65%, and mostpreferably 50-55%

Other oils: 5-15%, more preferably 7-15%, and most preferably 10-13%

Drug: 10-30%, more preferably 15-25%, and most preferably 18-22%.

The formulations of the present invention have self-emulsifyingproperties, forming a fine emulsion upon dilution with aqueous media orintestinal fluids in vivo. In other words, the formulations may havehigh surfactant and lipid content designed for optimum dispersion uponmixing with an aqueous medium. Qualitative description of theself-emulsification property of the inventive formulations can bevisually observed during the dissolution of same in vitro. On the otherhand, quantitative measurements may be taken of the particle size of theemulsified droplets using laser light scattering and/or turbiditymeasurements in the dissolution medium by UV/VIS spectrophotometer. Anyof these methodologies are available and known to one of ordinary skillin the art.

The pharmaceutical compositions according to the present invention arepreferably liquid or semi-solid at ambient temperatures. Furthermore,these pharmaceutical compositions can be transformed into solid dosageforms through adsorption onto solid carrier particles, such as silicondioxide, calcium silicate or magnesium aluminometasilicate to obtainfree-flowing powders which can be either filled into hard capsules orcompressed into tablets. See, e.g., US 2003/0072798, the disclosure ofwhich is incorporated in its entirety by reference. Hence, the term“solubilized” herein, should be interpreted to describe an activepharmaceutical ingredient (API), which is dissolved in a liquid solutionor which is uniformly dispersed in a solid carrier. Also sachet typedosage forms can be formed and used.

The instant invention preferably comprises an API that is solubilized inthe presence of lipid surfactant excipients (e.g., any combination ofthe lipophilic and hydrophilic surfactants noted above). Accordingly,the melting point of the surfactants used is one factor that candetermine whether the resulting composition will be liquid or semi-solidat ambient temperature. Particularly preferred compositions of thepresent invention are liquid oral unit dosage forms, more preferablyfilled into hard or soft capsules, e.g. gelatin or non-gelatin capsulessuch as those made of cellulose, carrageenan, or pollulan. Thetechnology for encapsulating lipid-based pharmaceutical preparations iswell known to one of ordinary skill in the art. As the inventivedelivery systems and formulations described herein are not limited toany one encapsulation method, specific encapsulation techniques need notbe discussed further.

The drug carrier systems and pharmaceutical preparations according tothe present invention may be prepared by conventional techniques forlipid-based drug carrier systems. In a typical procedure for thepreparation of the preferred carrier systems of this invention, alipophilic surfactant component is weighed out into a suitable stainlesssteel vessel and a hydrophilic surfactant component is then weighed andadded to the container along with any additional components. In apreferred method, the hydrophobic drug may be first added to alipophilic surfactant component (e.g., oleic acid) and completelydissolved before adding a hydrophilic surfactant component. In any case,mixing of the components may be effected by use of a homogenizing mixeror other high shear device and high temperature particularly when highmelting point surfactants are used to ensure that all components are inhomogenous liquid state before or after the addition of the drug.

In a situation in which a hydrophobic drug is weighed and added to acombined lipid mixture, mixing is continued, preferably at hightemperature, until a homogenous solution is prepared. The formulationmay be de-aerated before encapsulation in either soft or hard capsules.In some instances the fill formulation may be held at elevatedtemperature using a suitable jacketed vessel to aid processing. Also, insome instances, the homogenous solution may be filtered (e.g., through a5 micron filter) before filling into capsules.

Returning now to the delivery of testosterone, the pharmaceuticalcompositions of the present invention may be suitable for testosteronetherapy. Testosterone is the main endogenous androgen in men. Leydigcells in the testes produce approximately 7 mg of testosterone each dayresulting in serum concentrations ranging from about 300 to about 1100ng/dL. Women also synthesize testosterone in both the ovary and adrenalgland, but the amount is about one-tenth that observed in eugonadal men.The majority (≥98%) of circulating testosterone is bound to sex hormonebinding globulin and albumin and is biologically active only whenreleased in the free form. The term “free” is thus defined as not beingbound to or confined within, for example, biomolecules, cells and/orlipid matrices of the inventive formulations described herein.Generally, “free” medicaments described herein refer to medicament thatis accessible to metabolic enzymes circulating in serum.

While the present invention should not be limited to the delivery oftestosterone or any particular ester thereof, TU has been found to offerunique chemical and physical characteristics that make its usepreferable in some embodiments. The present inventors have learned thatthe undecanoate acid ester of testosterone, in particular, can yieldsuperior bioavailability to that found with other equivalent esters(e.g., testosterone enanthate (TE)).

What is more, the use of TU in the formulations of the present inventionis associated with a substantially lower serum DHT to T ratio than hasbeen reported for other forms of T replacement—including oralformulations of TU (Table 1). Testosterone interacts with androgenreceptors either directly or following its conversion to DHT via theaction of 5α-reductase. DHT is a more potent androgen than testosteroneand its elevated levels are thought by some scientists to increase therisk of prostate cancer. In this way, the present invention provides yetanother unexpected advantage over other known testosterone deliveryvehicles.

TABLE 1 Comparison of Serum DHT and DHT:T Ratios Observed in Response toT- Replacement by Various Routes of Administration Avg. Multiple SerumAvg. of Clarus Form of Androgen Length of DHT DHT:T DHT:TReplacement/Dose Exposure (ng/dL) Ratio Ratio Reference Oral TU in SEDDS 7-Days 107 0.24 1 [200 mg T (as TU), BID] Oral TU in SEDDS 30-Days 1090.25 1 [200 mg T (as TU), BID] Scrotal T-Patch (4-6 mg,  8 years 1750.42 1.75 Atkinson et QD) al (1998)¹ (Testoderm ®) Transdermal T-Gel  3years 130-210 0.25-0.30 1-1.25 Swerdloff (5-10 g, QD) et al (AndroGel ®)(2000)², Wang et al (2004)³ Oral TU (Andriol) [50 mg Several 93 0.40 1.7Houwing et T (as TU), BID] Months al (2003)⁴ Oral TU (Andriol) [50 mg 10years 90 0.50 2.1 Gooren et T (as TU), BID] al (1994)⁵ ¹Atkinson, LE,Chang, Y-L and Synder, PJ. (1998) Long-term experience with testosteronereplacement through scrotal skin. In: Testosterone: Action, Deficiencyand Substitution (Nieschlag, E and Behre, HM, eds). Springer-Verlag,Berlin, pp. 365-388 ²Swerdloff, RS, et a (2000). Long-termpharmacokinetics of transdermal testosterone gel in hypogonadal men. J.Clin. Endocrinol. Metab. 85: 4500-4510. ³Wang, C et al (2004). Long-termtestosterone gel (AndroGel ®) treatment maintains beneficial effects onsexual function and mood, lean and fat mass and bone mineral density inhypogonadal men. J. Clin. Endocrinol. Metab. 89: 2085-2098. ⁴Houwing, NSet al (2003). Pharmacokinetic study in women of three different doses ofa new formulation of oral testosterone undecanoate, Andriol Testocaps.Pharmcotherapy: 23: 1257-1265. ⁵Gooren, LJG (1994). A ten-year safetystudy of the oral androgen testosterone undecanoate. J. Androl. 15:212-215.

Specific embodiments of the instant invention will now be described innon-limiting examples. Table 2 provides composition details of variousformulations of TU, in accordance with the teachings of the instantinvention. For calculation purposes, 1 mg of T is equivalent to 1.58 mgT-undecanoate.

The compositions details of Table 2 (mg/capsule and wt. percentage) arebased on an approximate fill weight of 800 mg fill weight per ‘00’ hardgelatin capsule. However, at testosterone-ester amounts less than about100 mg/capsule, the formulations may be proportionally adjusted forsmaller total fill weights that would permit use of smaller hard gelatincapsules (e.g., size ‘0’ or smaller size if needed).

As well, it should be apparent to one of ordinary skill in the art thatmany, if not all, of the surfactants within a category (e.g.,lipophilic, hydrophilic, etc.) may be exchanged with another surfactantfrom the same category. Thus, while Table 1 lists formulationscomprising oleic acid, one of ordinary skill in the art should recognizeother lipophilic surfactants (e.g., those listed above) may be suitableas well. Similarly, while Table 1 lists formulations comprisingCremophor RH40 (HLB=13), one of ordinary skill in the art shouldrecognize other hydrophilic surfactants (e.g., those listed above) maybe suitable. Borage oil, peppermint oil, BHT, and ascorbyl palmitate maybe substituted for chemically similar substances or eliminated.

TABLE 2 Composition % w/w (mg/“00” capsule)¹ Fill Cremophor BoragePeppermint Ascorbyl Wt. F. TU Oleic Acid RH40 Oil Oil BHT Palmitate(mg)² 1  20   51.5 16 10 2.5 0.06 — 800 (158) (413)  (128.5) (80) (20)  (0.5) 2  15   54.5 18 10 2.5 0.02 0.8 806.6 (120) (436) (144)  (80)(20)   (0.2) (6.4) 3  17   52.5 18 10 2.5 0.02 0.8 806.6 (136) (420)(144)  (80) (20)   (0.2) (6.4) 4  19   50.5 18 10 2.5 0.02 0.8 806.6(152) (404) (144)  (80) (20)   (0.2) (6.4) 5  21  50 16.5  10 2.5 0.020.8 806.6 (168) (400) (132)  (80) (20)   (0.2) (6.4) 6  23  50 14.5  102.5 0.02 0.8 806.6 (184) (400) (116)  (80) (20)   (0.2) (6.4) 7  25  5012.5  10 2.5 0.02 0.8 806.6 (200) (400) (100)  (80) (20)   (0.2) (6.4) 8 16   53.5 18 10 2.5 0.02 0.8 806.6 (128) (428) (144)  (80) (20)   (0.2)(6.4) 9  18   51.5 18 10 2.5 0.02 0.8 806.6 (144) (413) (144)  (80)(20)   (0.2) (6.4) 10  22  50 15.5  10 2.5 0.02 0.8 806.6 (176) (400)(124  (80) (20)   (0.2) (6.4) 11  24  50 13.5  10 2.5 0.02 0.8 806.6(192) (400) (108)  (80) (20)   (0.2) (6.4) 12  15   55.5 17 10 2.5 0.020.8 806.6 (120) (444) (136)  (80) (20)   (0.2) (6.4) 13  17   53.5 17 102.5 0.02 0.8 806.6 (136) (428) (136)  (80) (20)   (0.2) (6.4) 14  19  51.5 17 10 2.5 0.02 0.8 806.6 (152) (412) (136)  (80) (20)   (0.2)(6.4) 15  15   56.5 16 10 2.5 0.02 0.8 806.6 (120) (452) (128)  (80)(20)   (0.2) (6.4) 16  17   54.5 16 10 2.5 0.02 0.8 806.6 (136) (436)(128)  (80) (20)   (0.2) (6.4) 17  19   52.5 16 10 2.5 0.02 0.8 806.6(152) (420) (128)  (80) (20)   (0.2) (6.4) 18  21   50.5 16 10 2.5 0.020.8 806.6 (168) (404) (128)  (80) (20)   (0.2) (6.4) 19  20   50.5 17 102.5 0.02 0.8 806.6 (160) (404) (136)  (80) (20)   (0.2) (6.4) 20  20  51.5 16 10 2.5 0.02 0.8 806.6 (160) (412) (128)  (80) (20)   (0.2)(6.4) 21  15   57.5 15 10 2.5 0.02 0.8 806.6 (120) (460) (120)  (80)(20)   (0.2) (6.4) 22  16   56.5 15 10 2.5 0.02 0.8 806.6 (128) (452)(120)  (80) (20)   (0.2) (6.4) 23  17   55.5 15 10 2.5 0.02 0.8 806.6(136) (444) (120)  (80) (20)   (0.2) (6.4) 24  18   (54.5 15 10 2.5 0.020.8 806.6 (144) (436) (120)  (80) (20)   (0.2) (6.4) 25  19   53.5 15 102.5 0.02 0.8 806.6 (152) (428) (120)  (80) (20)   (0.2) (6.4) 26  20  51.5 16   9.4 3.1 0.06 — 800 (158) (413)  (128.5) (75) (25)   (0.5) —27  20   51.5 16   10.6 1.9 0.06 — 800 (158) (413)  (128.5) (85) (15)  (0.5) — 28  20   51.5 16   11.2 1.2 0.02 0.8 806.1 (158) (413)  (128.5)(90) (10)   (0.2) (6.4) 29  20   51.5 16   11.8 0.6 0.02 0.8 806.1 (158)(413) (128.5 (95) (5)   (0.2) (6.4) 30  25  50   12.5   10.6 1.9 0.06 —800.5 (200) (400) (100)  (85) (15)   (0.5) — ¹Milligram weights roundedto nearest whole number; 800 (±10%) ²±8 mg

Preferred formulations of TU filled into size “00” capsules inaccordance with the present invention are:

Formulation A Ingredients mg/capsule %, w/w Testosterone 158.3 19.8Undecanoate Oleic Acid 413.1 51.6 Cremophor RH 40 128.4 16.1 Borage SeedOil 80.0 10 Peppermint Oil 20.0 2.5 BHT 0.2 0.03 Total 800 100

Formulation B Ingredients mg/capsule %, w/w Testosterone 158.3 19.8Undecanoate Oleic Acid 412.5 51.6 Cremophor RH 40 128.4 16.0 PeppermintOil 20.0 2.5 Borage Seed Oil + 80.0 10 0.03% BHT Ascorbyl 0.8 0.1Palmitate Total 800 100

In vivo and in vitro performance data of the formulations in keepingwith the invention will next be described. However, the scope of theinvention should not be limited to the following examples nor thespecific formulations studied in the examples.

Example 1—Single-Day Study

Formulation B was studied for its single-day pharmacokinetic profileupon once- or twice-daily administration to hypogonadal men. The studywas designed as an open-label, single-day dosing, sequential,cross-over, pharmakokinetic study. Twelve (12) hypogonadal men wereenrolled after giving written informed consent, and all 12 subjectscompleted the study. Each subject received a daily dose of Formulation Bas follows:

1. 200 mg T (as TU) QD, i.e., 2 capsules/dose

2. 200 mg T (as TU) BID (100 mg/dose), i.e., 1 capsule/dose

3. 400 mg T (as TU) BID (200 mg/dose)

The doses were administered as capsules to subjects five minutes after ameal (breakfast for QD, and breakfast and dinner for BID).

Table 3 provides the relevant PK parameters from the study:

TABLE 3 Single-Day Pharmacokinetic Parameters for T, DHT, and DHT:TRatio Means (Standard Deviations) of Pharmacokinetic Parameters^(a)Pharmacokinetic Regimen 2 Regimen 3 Parameter Regimen 1 (TU BID (TU BID(unit) (TU QD 200 mg^(b)) 100 mg^(b)) 200 mg^(b)) T AUC₂₄ 5907  6751 9252  (ng · hr/dL) (1840)  (2145)  (3173)  C_(avg) (ng/dL) 246 281 385(77)  (89) (132) T_(1/2) (hr)^(a)   15.5   15.1    8.0  (7.0-24.0)(4.5-43.4)  (4.2-16.3) C_(max) (ng/dL) 0-24 hrs: 0-12 hrs: 0-12 hrs: 557470 626 (252) (247) (267) 12-24 hrs: 12-24 hrs: 466 718 (160) (333)T_(max) (hr)^(a) 0-24 hrs: 0-12 hrs: 0-12 hrs:    4.0    4.0    4.0(2.0-8.0) (2.0-12.0)  (2.0-12.0) 12-24 hrs: 12-24 hrs:   16.0   16.0(14.0-20.0) (14.0-20.0) DHT AUC₂₄ 1097  1400  1732  (ng · hr/dL) (387)(758) (859) C_(avg) (ng/dL)   45.7   58.3   72.2   (16.1)   (31.6)  (35.8) C_(max) (ng/dL) 0-24 hrs: 0-12 hrs: 0-12 hrs: 122   81.3 108 (66)   (40.3)  (59) 12-24 hrs: 12-24 hrs:   97.9 114   (51.2)  (58)T_(max) (hr)^(a) 0-24 hrs: 0-12 hrs: 0-12 hrs:    4.0    4.0    4.0(1.0-8.0) (1.0-12.0)  (1.0-12.0) 12-24 hrs: 12-24 hrs:   16.0   16.0(13.0-20.0)  (14.0-20.0) DHT:T Ratio R_(avg) (ng/dL)    0.189    0.233   0.198    (0.070)    (0.137)    (0.041) ^(a)Values shown for half-lifeand time to maximum concentration are median and the range. ^(b)Dosesindicated are in T equivalents. Each TU capsule contained 158.3 mg TU,which corresponds to 100 mg T equivalents.

Mean serum T concentration during the 24-hour period post-dose (C_(avg))indicated positive increases in serum T levels for all regimens studied,with the best response obtained in Regimen 3 (C_(avg) 385 ng/dL). Meanpeak serum T concentration observed in response to the oral T-esterpreparations evaluated in this study never exceeded the upper limit ofnormal (i.e., 1100 ng/dL). And while some individual subjects did haveC_(max) T values above the normal upper limit, the vast majority ofthese peaks were in the range of 1200 to 1400 ng/dL. No subject in anytreatment arm experienced a C_(max) in excess of 1500 ng/dL.

Median serum T half-life (T_(1/2)) was approximately 15 hours forRegimens 1 and 2; for Regimen 3, T_(1/2) was 8 hours. In each regimen,serum DHT concentrations increased in concert with serum T levels. Themean DHT:T ratios (R_(avg)) in all periods were modestly above thenormal ranges as determined by liquid chromatography-mass spectroscopy(LC/MS/MS) (i.e., 0.03-0.1), but were clinically insignificant.

TU dosed at 200 mg T equivalents, BID with food yielded the mostpromising results with 75% of the subjects achieving a serum T C_(avg)above 300 ng/dL (lower normal eugonadal limit). Similarly, 75% of thesubjects achieved an average serum T within the normal range (i.e.,0.03-0.1 ng/dL). Those subjects that did not achieve a C_(avg) of atleast 300 ng/dL were all above 200 ng/dL, indicating that a modestincrease in the TU dose would have been effective oral T replacementtherapy in these subjects.

Serum T and DHT concentrations increased in concert in the majority ofsubjects regardless of T-ester dose with excellent dose linearity fororal TU was observed when data were corrected for serum T at baseline.Although DHT:T ratios were modestly elevated, any elevation wasconsidered clinically insignificant. Less inter-subject variability wasobserved with the formulation than equivalent formulations of otherT-esters (e.g., TE). Furthermore, in the “BID” dosing regimens, therewas no difference in mean peak serum T concentrations or in the 12-hourAUCs between the morning and evening dose.

Concerning safety, although headache was reported as an adverse effect,in each treatment regimen, no adverse event was reported by more thanone subject. No serious adverse events or deaths occurred during thestudy, and no subjects prematurely discontinued the study due to adverseevents. Hence, all adverse events were considered to be of mildintensity.

Example 2—Seven-Day Study

Formulation B was studied for its acute tolerability and steady-stateserum pharmacokinetic profile at two doses administered twice-daily tohypogonadal men. The study was designed as an open-label, repeat dose,cross-over, pharmacokinetic study (with food effect examined in onearm).

Twenty nine (29) hypogonadal men were enrolled after giving writteninformed consent, 24 of which completed the study. Each subject whocompleted the study received a regimen of Formulation B as follows:

1. 7 daily doses of 600 mg T as TU BID (300 mg/dose), i.e., 3capsules/dose

2. 8 daily doses of 400 mg T as TU BID (200 mg/dose)

Doses were administered as capsules to subjects 30 minutes afterinitiation of meals (breakfast and dinner), except for Day 8, when themorning dose was administered fasting.

Peak exposure (C_(max)) to T and total exposure (AUC) to T were doseproportional after correction for the endogenous baseline T. The time ofpeak T concentrations (T_(max)) occurred at approximately 4 hourspost-dose with each of the treatments. As well, the serum concentrationsof both TU and DHTU rise and fall within the dosage interval withconcentrations at the beginning and end of the dosing interval beingless than 20% of the peak concentration for TU and less than 25% of thepeak concentration for DHTU. Baseline T concentrations due to endogenousT production decreased progressively for each treatment. The observationis consistent with a progressive and persistent suppression ofgonadotropins by exogenous T, thereby resulting in a decreasedproduction of endogenous T. At least partial suppression was maintainedover a 14-day washout period.

Again, serum T pharmacokinetics did not show diurnal variation withserum T concentrations. The night dose (administered at approximately 8PM) produced a similar concentration-time profile as the morning dose(administered at approximately 8 AM) (FIG. 1). On account of thesimilarity between concentrations after AM and PM dosing (assessed inRegimen 1), 12-hour PK data from Regimen 2 (fed) were used to accuratelypredict a full 24-hour PK profile in response to 200 mg T (as TU), BIDdosing. The simulated results indicated that (a) 77% of the subjectsachieved a serum T C_(avg) in the eugonadal range over the 24-hourperiod based on AUC thereby meeting the current FDA efficacy requirementof 75% for a T-replacement product; and (b) none of the subjectsexperienced a C_(max) in excess of 1500 ng/dL, which is exceeds currentFDA criteria that less than 85% of subjects have a C_(max) of greaterthan 1500 ng/dL for a T-replacement product. Hence, also consistent withcurrent FDA mandated efficacy endpoints, no subjects had a C_(max) inexcess of 2500 ng/dL and less than 5% of the subjects studied had aC_(max) in the range of 1800-2500 ng/dL. It is noteworthy that theseresults were achieved in the absence of any dose adjustment.

TABLE 4 Treatment Regimen 1 300 mg T, as TU, BID AM Dose PM Dose Mean ±SEM Mean ± SEM C_(max) (ng/dL) 1410 ± 146  1441 ± 118  T_(max) (hr, timeafter dose) 4.50 ± 0.39 5.9 ± 0.5 C_(min) (ng/dL) 305 ± 30  324 ± 36 AUC₀₋₁₂ (ng · hr/dL) 9179 ± 754  9830 ± 659  C_(avg) (ng/dL) 765 ± 63 819 ± 55  FI ratio 1.37 ± 0.09 1.36 ± 0.09 C_(min)/C_(max) ratio 0.256 ±0.029 0.243 ± 0.022

Administration of TU with a high-fat meal produced a similar serumT-concentration-time profile as administration with a standard meal. Incontrast, administration of TU under fasting conditions resulted ingreater than 50% decrease in serum T exposures (C_(max) and AUC). Table5. In all cases, a strong correlation between the observed C_(max) andthe calculated C_(avg) was observed, suggesting that targeting of aparticular C_(avg) with the oral T-ester formulation can result inpredictable peak T levels after dosing.

TABLE 5 After High Fat Breakfast While Fasting Arithmetic GeometricArithmetic Geometric Geometric Mean of Mean Mean Mean Mean IndividualRatios C_(max) (ng/dL) 955 854 394 365 0.426 AUC₀₋₁₂ (ng · hr · dL) 62175682 2894 2692 0.471 Administration under fed conditions (high fatbreakfast) was used as the reference

DHT concentrations tracked T concentrations, although DHT concentrationswere only 11-34% of the T concentrations. Conversion of T to DHT showeda slight nonlinearity, increasing at a less than aconcentration-proportional rate compared to T. The DHT/T ratio was leastwhen T concentrations were highest, and the DHT/T ratio prior tostarting TU treatment was approximately 0.1, while during treatment, atsteady-state, the mean ratio was 0.24 and ranged from approximately 0.1to 0.35 depending on the time of sampling after oral TU wasadministered.

Mean estradiol concentration prior to starting the oral TU treatment wasapproximately 11 pg/mL, and ranged from 19 pg/mL to 33 pg/mL on Day 7 ofthe various treatments (pre-dose concentrations). Pre-dose steady-stateestradiol concentrations were approximately 20-30 pg/mL.

Example 3—Four-Week Study

Formulation B was also studied was to determine the time required toreach steady-state when hypogonadal men are treated for 28 days withtwice daily dosing of 200 mg T (as TU) (i.e., 2 capsules/dose). Thestudy was designed as an open-label, repeat dose, pharmacokinetic study.

Fifteen (15) hypogonadal men were enrolled after giving written informedconsent, and all completed the study. Each subject received twice-dailydoses of 200 mg T as TU for 28 days.

For each subject, the “Day 28” serial PK sampling day was scheduled forDay 32 of the study. Therefore, each dose-compliant subject received atotal of 31 daily doses of 400 mg T as TU (i.e., 200 mg T, BID), and afinal morning dose of 200 mg T as TU. Doses were administered ascapsules, with subjects instructed to take doses 30 minutes afterinitiation of meals (breakfast and dinner).

TABLE 6.^(a) T DHT DHT/T E₂ C_(max) 995 ± 436 151 ± 75  0.380 ± 0.18130.6 ± 14.9 or (43.9%) (49.5%) (47.7%) (48.7%) R_(max) ^(b) ng/dL ng/dLratio pg/mL T_(max) 4.87 ± 1.96 5.87 ± 2.80 5.87 ± 6.02 6.67 ± 3.09(40.3%) (47.7%) (102.7%)  (46.3%) hr hr hr hr C_(min) 199 ± 108 64.6 ±47.6 0.131 ± 0.047 15.4 ± 9.2  or (54.2%) (73.8%) (36.0%) (59.9%)R_(min) ^(b) ng/dL ng/dL ratio pg/mL C_(avg) 516 ± 226 109 ± 61  0.245 ±0.077 22.0 ± 10.9 or (43.7%) (55.8%) (31.5%) (49.8%) R_(avg) ^(b) ng/dLng/dL ratio pg/mL AUC₀₋₁₂ 6197 ± 2708 1312 ± 732  2.94 ± 0.93 264 ± 131(43.7%) (55.8%) (31.5%) (49.8%) ng · hr/dL ng · hr/dL hr pg · hr/mLC_(min)/C_(max) 23.5% ± 16.2% 41.5% ± 17.0% 37.3% ± 11.5% 50.2% ± 15.1%or (69.0%) (40.9%) (30.8%) (30.0%) R_(min)/R_(max) ^(b) % % % % Absolute−168 ± 188   3.50 ± 16.80 0.197 ± 0.116 −0.405 ± 5.345  Change in(112.2%)  (480.1%)  (59.0%) (1320.8%)  C_(baseline) ^(c) ng/dL ng/dLratio pg/mL Percent −53.4% ± 79.5%  18.8% ± 95.0% 267% ± 170% −1.9% ±41.5% Change in (148.8%)  (506.6%)  (63.8%) (2224.6%)  C_(baseline) ^(c)% % % % Fluctuation 156% ± 64%  84.7% ± 30.6% 96.0% ± 29.7% 74.5% ±41.6% Index (40.8%) (36.1%) (30.9%) (55.9%) % % % % λ_(z) 0.0726 ±0.0676 0.0793 ± 0.0373 NA 0.0544 ± 0.0176 (93.1%) (47.1%) (32.4%) 1/hr1/hr 1/hr T_(1/2) 29.0 ± 32.7 10.8 ± 5.8  NA 14.0 ± 5.3  (112.8%) (53.6%) (37.8%) hr hr hr ^(a)Results expressed as mean ± SEM.Co-efficient over variation is expressed as % in parentheses.^(b)R_(max), R_(min), R_(avg) are the Maximum ratio, the Minimum ratioand the Time Averaged ratio, respectively for the DHT/T ratio (analogousto C_(max), C_(min) and C_(avg)) ^(c)Change in Baseline determined asconcentration (or ratio) in the final sample of Day 28 - concentration(or ratio) in the pre-treatment sample (Day 0).

86.7% of subjects achieved serum T C_(avg) within the normal range, withno subjects having C_(max) concentrations greater than 1800 ng/dL, andwith just 13.3% of subjects having C_(max) concentrations greater than1500 ng/dL. (Note: No dosing adjustments were made during the conduct ofthis study to titrate subjects to be within the targeted efficacy andsafety ranges.) The half-life of T in response to TU in the formulationtested was appreciably longer than has been reported for T alone or forTU given orally in prior art formulations. For example, in clinicalstudies of an oral TU formulation consistent with the inventiondescribed herein, an elimination half-life (a phase) of aboutapproximately 5 hours was observed compared to a value estimated to beroughly half that (i.e., 2 to 3 hours) based on published serum Tprofiles after oral dosing of a prior art formulation of TU. A longelimination (i.e., terminal) half-life of 29 hrs was also observed withthe inventive oral TU formulation. Endogenous T production wassuppressed, however, by the administration of exogenous T, with onlylimited suppression occurring for the first 3 days, and requiring 5-7days of continued treatment for maximal suppression.

Concentrations of T and DHT reached steady state by Day 7 of treatment.Concentrations of T and DHT were greater on Day 3 than on Day 5,indicating that a period of time was required for the exogenouslyadministered T to suppress endogenous T production thus enablingachievement of steady-state in response to oral TU. Indeed, addition ofthe exogenous T suppressed endogenous T levels from 276 ng/dLpretreatment to 108 ng/dL after 28 days of supplementary T treatment.

Significantly, however, once steady state was achieved for serum T inresponse to twice-daily oral TU, little to no decline in serum Tresponse was observed over time (i.e., no trend toward lower serum Tlevel with continued TU dosing). For example, the C_(avg) at Day 15 wassubstantially similar to the C_(avg) observed at day 28 (FIG. 2). Bycontrast, oral TU formulations in the art have been reported to trendtoward a lower mean T over time (Cantrill, J. A. Clinical Endocrinol(1984) 21: 97-107). In hypogonadal men treated with a formulation oforal TU, known in the art, it has been reported that the serum Tresponse observed after 4 weeks of therapy was about 30% less than thatobserved on the initial day of therapy in hypogonadal men—most of whomhad a form of primary hypogonadism and thus low baseline levels of serumT (e.g., <100 ng/dL), so the decrease in T cannot be explained bysuppression of endogenous T alone].

Serum DHT concentrations closely tracked T concentrations, with DHT andDHT/T values increasing 4 to 7 fold during treatment. Average DHT/Tratio over a 12-hour dosing interval was 0.245, although values over thedosing interval ranged from a mean maximum ratio of 0.380 to a meanminimum ratio of 0.131. DHT concentrations returned to pretreatmentlevels within 36 hours of discontinuing treatment with oral TU. However,T concentrations did not return to pretreatment levels as quickly,ostensibly because of the suppression of endogenous T production/releaseis not as rapidly reversed.

Concentrations of estradiol (E2) showed a monotonic, progressiveincrease to the steady state, which was also reached by Day 7 oftreatment. E2 concentrations also showed systematic variation over thedosing interval that tracked the changes in T. The mean C_(max),C_(avg), and C_(min) values for E2 were 30.6 pg/mL, 22.0 pg/mL and 15.5pg/mL, respectively. E2 concentrations returned to pretreatment levelswithin 36 hours of discontinuing treatment with oral TU.

Mean C_(max), C_(avg), and C_(min) concentrations at steady state(morning dose of Day 28) for T were 995 ng/dL, 516 ng/dL and 199 ng/dL,respectively. Median Tmax for T occurred at 5.0 hours post dose. C_(min)averaged 23.5% of C_(max), resulting in a Fluctuation Index of 156%. Theelimination half-life of T could only be evaluated in about half thesubjects, and its median value in those subjects was 18.4 hours (meanT_(1/2) was 29 hours).

Example 4—Food Effects Study

Any effect of dietary fat on the pharmacokinetics of Formulation B inhypogonadal men was studied in an open-label, two-center, five-waycrossover study. After a washout period of 4-10 days, a single dose of300 mg of T (475 mg TU, 3 capsules of Formulation B) was administered tosixteen hypogonadal men with serum a baseline T level 205.5±25.3 ng/dL(mean±SE, range 23-334.1 ng/dL). Subjects were randomized to receive thedrug in the fasting state or 30 minutes after consumption of mealscontaining ˜800 calories with specific amounts of fat (wt %): very lowfat (6-10%); low fat (20%); “normal” diet fat (30%); or high fat (50%).The “normal” diet was, a priori, established as the comparator (i.e.,reference diet) for purposes of statistical comparisons. Serial bloodsamples were collected for a total of 24 hours after drug administrationto determine serum testosterone and dihydrotestosterone (DHT) levels byliquid chromatography-mass spectroscopy (LC/MS/MS).

Pharmacokinteic parameters (Table 7, FIGS. 3-5) observed for serum T inresponse to a single, high-dose of oral TU were found to be similar fora low-fat and normal fat diet—in fact so much so that they werebioequivalent (i.e., the 90% confidence interval was between 85-125%).Similar serum T PK parameters were also observed when the normal- andhigh-fat meals were compared. And although the high-fat meal yielded agreater serum T response (albeit not statistically different), the meanratio of least square means fell within 70-143% when compared to thenormal-fat meal—a clinically insignificant difference of <30%.

TABLE 7 Serum T pharmacokinetic parameters (mean ± SD) in response tooral TU administered with different diets Fasting 6-10% Fat 20% Fat 30%Fat 50% Fat C_(Avg) ¹ (ng/dL) 526 ± 324 781 ± 385 884 ± 505 1010 ± 3561260 ± 477 C_(Max) (ng/dL) 948 ± 798 1370 ± 732  1520 ± 711  1760 ± 5982140 ± 901 T_(Max) (hr)  4.1 ± 0.96 4.9 ± 1.8 6.3 ± 3.9  5.1 ± 1.5  6.4± 4.9 AUC (ng * h/dL) 7796 ± 3673 10855 ± 4285  12477 ± 5028  13639 ±3773 16464 ± 5584 ¹C_(Avg) is calculated as AUC_(0-∞)/τ (τ = dosinginterval = 12 hours for BID dosing)

Variability in PK response appeared to be highest following the firstdose, or first few doses of oral TU, and decreased as therapy continued.Consequently, any impact of dietary fat across the range oflow-normal-high on serum T PK parameters is likely to be insignificantduring chronic dosing. This stance is consistent with the PK findingsfrom the 7-day treatment (Example 2) and from the 30-day treatment(Example 3), where repeat dose studies of oral TU where the PK under thediffering meal conditions still showed similar results for Cmax and Cavgdistributions [both studies administered 200 mg T (as TU), BID].

Statistical comparisons of the serum T response observed after oral TUwas taken without food or with a very low fat, low fat, or high fat dietversus a normal fat diet (i.e., reference diet) revealed that there wasno statistically significant difference at the p<0.05 level between thelow-fat or high-fat diets versus the normal diet. Conversely,administration of oral TU as a SEDDS formulation while fasting or with avery low-fat breakfast yielded serum T PK parameters significantlydifferent (i.e., lower) from a normal diet. Accordingly, the fat contentof meals taken with the inventive formulations can differ substantiallyfrom “normal”, without a clinically significant impact on the levels ofT obtained. Thus, a patient is permitted flexibility in eating habitsfrom meal to meal, and from day to day, which could not have beenheretofore possible with known oral TU formulations. Oral TUformulations known in the art have heretofore been unable to achieve anymeaningful serum T levels in the fasted state.

Example 5—In Vitro Dissolution Tests

Dissolution studies of formulations of the present invention werestudied in vitro to assess their correlation with the PK profilesobserved in vivo. In a first study, the dissolution of Formulation B wasstudied. Andriol Testocaps® (40 mg TU per softgel dissolved in a mixtureof castor oil and propylene glycol laurate) was included for comparison.The study was conducted with essentially equivalent doses of TU, i.e., 1capsule of Formulation B (158.3 mg TU) and 4 softgels of Testocaps (4×40mg=160 mg TU). The dissolution (i.e., the release of TU from therespective formulations) was studied in Fed State Simulated IntestinalFluid (FeSSIF) medium, which simulates intestinal fluid upon stimulationby a meal. FeSSIF contains sodium hydroxide, glacial acetic acid,potassium chloride, lecithin, and sodium taurocholate. The finalemulsion is adjusted to pH 5.0.

That data are presented in Tables 8 and 9 demonstrate that the inventiveformulation released approximately 40% TU within the first 30 minutesand about 60% of the total capsule after 4 hours. For the Testocaps®,however, there is little to no drug released (1%) for the entire 4hours. The observed major difference in the dissolution of TU from thesetwo formulations can be attributed, at least in part, to the presence ofthe hydrophilic surfactant, e.g., Cremophor RH40, in Formulation B. Incontrast, Andriol Testocaps® (incorporate an oil (Castor Oil) and alipophilic surfactant (Propylene Glycol Laureate) only.

TABLE 8 % Release of TU from Formulation B Time % Released (Hours) 1 2 3Average 0.5 39.3 39.2 34.6 37.7 1 46.2 43.6 44.3 44.7 2 52.8 50.9 49.851.2 4 62.7 61.7 61.3 61.9 Infinity 96.0 100.1 90.9 95.6

TABLE 9 % Release of TU from Andriol Testocaps ® Time % Released (Hours)1 2 3 Average 0.5 0.0 0.0 0.0 0.0 1 0.0 0.0 0.0 0.0 2 0.0 0.9 0.0 0.3 41.3 1.1 1.3 1.3 Infinity 3.9 3.6 1.5 3.0

In a second study, Formulation A was subjected to a similar assay, butusing a 5% Triton X100 potassium phosphate buffer (pH 6.8) as adissolution medium. The results are provided in Table 10 below. In thisstudy, 98% of the TU from the inventive formulation was released withinthe first 15 minutes of dissolution and once again the presence of thehydrophilic surfactant Cremophor RH40 has certainly facilitated thisfast dissolution and TU release.

TABLE 10 % Release of TU from Formulation A Time % Released (M) 1 2 3 45 6 Average 0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 .25 98.9 96.9 97.7 95.7 96.6101.0 97.8 0.5 98.9 97.8 98.4 98.3 97.5 100.0 98.5 1.0 99.5 98.2 98.098.4 98.1 100.2 98.7

In yet another embodiment of the present invention, the pharmaceuticalcompositions disclosed herein may also be suitable for ameliorating someof the side-effects of certain strategies for male contraception. Forexample, progestin-based male contraception substantially suppressesluteinizing hormone (LH) and follicle-stimulating hormone (FSH), andthereby suppresses spermatogenesis, resulting in clinical azoospermia(defined as less than about 1 million sperm/mL semen for 2 consecutivemonths). However, administration of progestins also has the undesirableside-effect of significantly reducing steady-state serum testosteronelevels.

In such situations, for example, it may be preferable to providepreparations of progestin concomitantly with testosterone or atestosterone derivative (e.g., TU). More preferably, a pharmaceuticalpreparation according to the invention is provided, comprisingprogestin—in an amount sufficient to substantially suppress LH and FSHproduction—in combination with testosterone. In some embodiments, thepharmaceutical preparation is for once-daily, oral delivery.

Formulations of the present invention can provide extended releaseformulations that can deliver testosterone into the serum over severalhours. Indeed, the half-life of serum testosterone according to theinvention is between 3 and 7 hours, preferably greater than 4, 5, or 6hours. The serum half-life of testosterone in men, by contrast, isconsidered to be in the range of 10 to 100 minutes.

Without being bound by or limited to theory, it is believed that theinventive formulations achieve these results, in one aspect, byenhancing absorption of a medicament therein by the intestinal lymphaticsystem rather than by way of portal circulation. In another aspect,again without being bound by or limited to theory, it is believed thatby using an ester of testosterone, the time required forde-esterification to occur contributes to a longer T half-life.

Oral dosages of the present invention can be taken by a patient in needof testosterone therapy once every about twelve hours to maintaindesirable levels of serum testosterone. In a more preferred embodiment,oral dosages are taken by a patient in need of testosterone therapy onceevery about twenty four hours. In general, “desirable” testosteronelevels are those levels found in a human subject characterized as nothaving testosterone deficiency.

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or alterations of the invention following. In general, theprinciples of the invention and including such departures from thepresent disclosure as come within known or customary practice within theart to which the invention pertains and as may be applied to theessential features hereinbefore set forth and as follows in the scope ofthe appended claims.

We claim:
 1. A method for treating a hypogonadal male comprising orallyadministering to the male twice-daily a composition comprising a capsuleand a liquid formulation encased within the capsule, the formulationbeing a self-emulsifying drug delivery system comprising a) 18-22percent by weight of testosterone undecanoate (TU), h) 12-18 percent byweight of hydrophilic surfactant, and c) 50-65 percent by weight oflipophilic surfactant, wherein the weight ratio of the total amount oflipophilic surfactant to the total amount of hydrophilic surfactant isabout 6:1 to about 3.5:1, wherein the total TU administered per dayranges from about 316 mg TU to about 948 mg TU, and wherein thecomposition, when orally administered to a plurality of hypogonadalmales, provides, at steady state, an average serum testosteroneconcentration Cave of from about 300 to about 1100 ng/dl in at least 75%of the males, a serum testosterone Cmax value of from 1800 to 2500 ng/dlin less than 5% of the males, a serum testosterone Cmax value that doesnot exceed 1500 ng/dl in at least 85% of the males, and a serumtestosterone Cmax value that does not exceed 2500 ng/dl in any of themales.
 2. The method according to claim 1, wherein administration of thecomposition provides a serum Tmax at 3 to 7 hours.
 3. The methodaccording to claim 1, wherein the Cave in the plurality of hypogonadalmales is proportional to the amount of testosterone undecanoate orallyadministered to the males.
 4. The method according to claim 1, whereinthe formulation further comprises a 5-alpha reductase inhibitor.
 5. Themethod according to claim 1, wherein the formulation further comprises aP450 isozyme CYP3A4 inhibitor.
 6. The method according to claim 1,wherein the formulation further comprises a digestible oil.
 7. Themethod according to claim 6, wherein the digestible oil comprises 10-15percent by weight of the formulation.
 8. The method according to claim7, wherein the hydrophilic surfactant is polyoxyethylene (40)hydrogenated castor oil and the lipophilic surfactant is oleic acid. 9.The method according to claim 1, wherein the composition releases about40 wt. % TU within the first 30 minutes and about 60 wt. % TU after 4hours when evaluated in Fed State Simulated Intestinal Fluid mediumcontaining sodium hydroxide, glacial acetic acid, potassium chloride,lecithin, and sodium taurocholate at a pH of 5.